Diet, especially a high-fat diet, has far-reaching effects on the health and well-being of the American people. Obesity, a major health problem, is manifested by fat deposited in the adipose from food not metabolized as energy. Metabolic syndrome covers many cardiovascular risk factors that collectively cause development of heart and brain diseases and type 2 diabetes. Calorie restriction or starvation promotes glycogenolysis that supplies glucose where needed and lypolysis that supplies fatty acids for oxidation and energy production. Insulin and glucagon are hormones that coordinate these processes. Recent studies point to malonyl-CoA, generated by acetyl-CoA carboxylases 1 and 2 (ACC1 and ACC2) as the potential factor that affects, in a concerted manner, other cardiovascular factors associated with the metabolic syndrome. Malonyl-CoA is synthesized through carboxylation of acetyl-CoA, the product of pyruvate dehydrogenase; hence, studies of the carboxylases interrelate three metabolic pathways: carbohydrate metabolism, fatty acid synthesis, and fatty acid oxidation. The differential expression of ACC1 and ACC2 in various tissues suggests that they may have different functions. We showed that ACC2 is associated with the mitochondria, and through its product, malonyl-CoA, regulates fatty acid oxidation. ACC1 is located in the cytosol and generates malonyl-CoA for the synthesis of fatty acids. Results from knockout mouse models of ACC1 and ACC2 support the hypothesis that ACC1 and ACC2 play distinct and different roles in animal physiology and energy metabolism. A mutation in ACC1 led to embryonic lethality. Knocking out ACC1 in specific tissues like liver, pancreas, or adipose has generated mice that we will use to study the role of malonyl-CoA and newly- synthesized fatty acids in the functions of these tissues, for instance, the release of insulin in the pancreas. Knocking out ACC1 in adipose generated mice with immature adipocytes, retarded growth, and that weiged less than their wild type cohorts. Acc2-/- mutant mice had normal lifespans, higher fatty acid oxidation rates, accumulated less fat in their liver and adipose tissues, and resisted type 2 diabetes compared to wild-type cohorts. Mating Acc1 Cre mice with Acc2-/- mice will help us evaluate the contributions of ACCs to their wellbeing. Studying the mechanism of ACC1 and ACC2 and development of.inhibitors of their calalysis may provide the means to regulate metabolism and design a therapeutic intervention.